The radiolabelling of (bio)molecules with Fluorine-18 (18F), is widely spread. A common PET diagnostic probe is [18F]-labeled fluorodeoxyglucose ([18F]-FDG):
[18F]-FDG is widely used for early detection of cancer.[18F]-FDG is routinely obtained by direct labelling of a mannose derivative via nucleophilic substitution.
Similarly to the carbohydrates, the peptides, proteins and the largest part of biomolecules contain numerous labile protons due to the presence of different functional groups such as hydroxyls, amides, amines, thiols, acids. However, for these kinds of macromolecules, a chemical protection of all of the functional groups cannot always be envisaged. Therefore, most often the direct labelling of these (bio)molecules by direct nucleophilic substitution cannot be performed.
The introduction of a radionuclide such as Fluorine-18 into a (bio)macromolecule of different nature, e. g. peptides, proteins, oligonucleotides, oligosaccharides is most often carried out via a prosthetic group bearing the radioisotope. This approach then involves the preparation of a functionalized and radiolabelled prosthetic compound followed by its conjugation with a specific reactive function of the (bio)macromolecule. This strategy has the advantage of making it possible to use severe conditions for the preparation of the radiolabelled prosthetic compound followed by its conjugation to the macromolecule under mild conditions preserving the integrity of the macromolecule.
A certain number of prosthetic compounds (also called prosthetic groups) labelled with Fluorine-18 are described in the literature. They can be classified according to their own reactive function and/or according to the reactive function present on the macromolecule they will react with (amines, hydrazines, oximes, acids, aldehydes etc.). Some of the prosthetic groups are designed to be coupled directly to a peptide or a protein via formation of an amide linkage using an amine function of an amino acid residue (e.g. N-terminal α-NH2 or internal ε-NH2 of a lysine) or optionally via any other spacer containing an amino function. In these cases, the prosthetic groups are characterized by a carboxylic function (e.g. [18F]-FBA) usually activated as an active derivative (e.g. succinimidyl or nitrophenyl ester of the corresponding carboxylic acid).
All these radiolabelled prosthetic compounds are characterized by different synthesis criteria such as the nature and ease of synthesis of the radiolabelling precursor, the effectiveness of the fluorination stage, the total number of radiosynthesis stages, the time of synthesis, their overall radiochemical yield, the ease of purification, their effectiveness in the conjugation reaction and the in vivo stability of the corresponding bioconjugates.
Moreover, the large scale production of these radiolabelled compounds is faced with constraints related to the complete automation of their synthesis. In fact, a complete automated synthesis of those radiolabelled compounds will satisfy both the pharmaceutical standards procedures (GMP), as well as the radiological protection requirements. Therefore an ideal manufacturing procedure will be characterized by few and easy synthesis and purifications steps.
Here below are shortly reported the synthesis of two of the prosthetic groups described in the literature:                the [18F]-SFB (N-succinimidyl 4-[18F]-fluorobenzoate ester):        

Recently, EP2404903A1 described a three-step automated method for synthesizing [18F]-SFB using microsynthesis technique:

Where:
“K222” corresponds to (4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane
“TSTU” corresponds to: (O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.
Even if this automated radiosynthesis leads to reasonable radiochemical decay corrected yields (60%), it has several disadvantages. It is not so easy to separate the labelled intermediate (fluoro benzoic ester) from the by product originated from the ammonium precursors. Moreover, the large number of steps and the necessity to purify each intermediate make the automation of this process difficult even if it is necessary to reach the Good Manufacturing Practice conditions.
A further not insignificant drawback is the lipophilic character of [18F]-SFB reagent which makes difficult its “wet” conjugation to water-soluble amine-containing biomolecules and the purification step (HPLC or solid-phase extraction) of the resulting [18F]-labelled molecular bioprobes.                The [18F]-SFS (1-{4-[(2,2-dioxido-1,2-oxathiolan-3-yl)carbonyl]phenyl}-4-fluoro-1-oxobutane-2-sulfonic acid):        

WO2011/018467A1 relates to polysultone derivatives used as precursors to radiolabelled macromolecules for medical applications especially in nuclear imaging and therapy.                Non radiolabelled Precursors        
                (Radio)labelled intermediates (prosthetic groups)        
                                    Where Ri is e.g. a radioelement or an NIR (Near Infra Red) agent            Where M is e.g. a generic cation                        Labelled (bio)conjugates        

The main advantage of these polysultones is that they can be coupled with a large sort of (bio)molecules. In fact, they can be used not only for the coupling with amino functions but also with thiol and hydroxyl functions. The fast hydrolysis of these polysultone derivatives represents the main disadvantage of those prosthetic groups.